Venetoclax in Relapsed/Refractory Myeloma: The BELLINI Trial

Transcript:

Sagar Lonial, MD, FACP: Tom, I know you’ve always had a lot to say about venetoclax. There were data, or at least a press release, that came out about venetoclax and bortezomib. There were interesting data. My colleague Larry Boise, PhD, has thoughts about why we may have seen what we saw. But do you want to summarize what we know and where you think venetoclax is going to go?

Thomas G. Martin, MD: Sure. I’ve always been impressed with the responses that we’re seeing with venetoclax. As a single agent in patients who have relapsed disease with the 11;14 translocation, and likely higher expression of the B-cell 2 pathway, the response rate of the single agent is 40%. Pretty impressive for an oral agent. But also, we’ve seen responses when patients who don’t have the 11;14 translocation but have relapsed disease get venetoclax together with bortezomib and dexamethasone. That led to the BELLINI trial, which is a phase III trial, and the phase III trial was bortezomib and dex [dexamethasone] versus venetoclax, bortezomib, and dex [dexamethasone].

Sagar Lonial, MD, FACP: In everybody? It was not an 11;14 trial.

Thomas G. Martin, MD: Correct. This is everybody, all-comers.

Sagar Lonial, MD, FACP: Right.

Thomas G. Martin, MD: And although there were better responses in the triplet versus the doublet arm, they actually saw a 2-fold increase in deaths. And most of the deaths were cardiovascular deaths, and were deaths from sepsis and pneumonia, which is quite interesting actually. Maybe there is some immune suppression affects from venetoclax together with bortezomib and dexamethasone.

We’ve treated a fair number of people off protocol at UCSF [University of California San Francisco]. We honestly didn’t follow everybody so intently like you do on a clinical trial. But offhand I don’t remember seeing a death or an infection that said to me, “Wow, this is an interesting or a difficult combination.” So I’m very puzzled actually by the data and I’m looking to see more data. And, apparently, we may actually have an abstract presented at EHA [European Hematology Congress] this year.

Sagar Lonial, MD, FACP: And it wasn’t just that responses were better, PFS [progression-free survival] was better. It was a significant improvement. And what I think Larry Boise, who spent a lot of time thinking on this, would argue is that it’s really the dex [dexamethasone] that is the better partner, or is the great partner with bortezomib or with venetoclax. And with bortezomib you may be getting a bystander affect, but you also may be getting an adverse event signal through, as you suggested, immune suppression. I’m curious, how do you all use this or think about using it, or have you completely stopped?

Saad Z. Usmani, MD, FACP: No, we’re still using it. And it’s interesting. I actually agree with Tom’s experiences, and we’ve been using venetoclax in combination with PI’s in patients who were more advanced than the BELLINI population, and we haven’t inherently observed this phenomenon of cardiovascular toxicity or these infections. So I’m really curious to what happened. Was it just a perfect storm? I’m attentive in looking at the data. It sounds very much like the pembro [pembrolizumab] story to me.

Amrita Y. Krishnan, MD: I’m not as close to the data as you are, but a lot of those deaths came off treatment as well?

Thomas G. Martin, MD: Some time after they came off therapy, yes. That said, the experimental arm had many more deaths than just bortezomib and dexamethasone. And so, we have to see what the etiology of that is. We have to follow it up.

Sagar Lonial, MD, FACP: I think certainly the pembro [pembrolizumab] story didn’t have the response benefit, and it didn’t have the PFS benefit.

Thomas G. Martin, MD: So right.

Sagar Lonial, MD, FACP: So, I don’t know that I want to paint it with the same brush.

Saad Z. Usmani, MD, FACP: No, no. I’m talking about the philosophical question of what we expect, we saw anecdotal experience at our individual sites, as well as the Phase I, II data, which were promising, and then we were unable to reconcile what really happened on the pembro [pembrolizumab] trials. And hopefully I think venetoclax has a future in myeloma therapy. There’s certainly a strong scientific rationale compared with say pembro [pembrolizumab], for example. So, I’m curious to learn about these data so we can tease out how to find the best population. Translocations 11;14s are definitely it, so I’m hoping that we can actually at least move forward in that patient population.

Sagar Lonial, MD, FACP: Krina, your center has had a lot of experience with PIs [protease inhibitors], so in general, do you guys have any thoughts or theories about what that interaction might be, or how does it fit in your treatment approach?

Krina K. Patel, MD, MSc: We’ve been talking about different mechanisms of potential resistance. I think the relapses and the patients who did relapse potentially were a little bit more aggressive. And so does this change the biology? What is it doing? So there are theories but I don’t think anyone really knows what.

We still use venetoclax and we’ve had patients, 11;14, BCL2-high expressors, who are responding. But now we put everybody on antibiotics. And so that’s the issue right? Hopefully this does open back up, these trials open, but what do you do now? If we don’t get a reason, do we put everyone on antibiotics? Well I think it’s fine for our relapsed-refractory patients. But if we’re moving it up, you can’t keep people on antibiotics forever. I think that’s the other clinical struggle that we’re all having. So, hopefully we get an answer, so we know if maybe it’s just a couple of cycles, or depending on where, what you partner with.

Saad Z. Usmani, MD, FACP: And I don’t think that any immunologic data were collected on the BELLINI patients, so that’s the other issue. We cannot determine whether there was a qualitative defect or a quantitative defect. What was it really that’s driving this?

Thomas G. Martin, MD: More data on June 3rd when the abstracts are released for EHA.

Sagar Lonial, MD, FACP: All right, good.

Transcript Edited for Clarity